Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
Hannah Kapell, … , Sven G. Meuth, Lucas Schirmer
Hannah Kapell, … , Sven G. Meuth, Lucas Schirmer
Published January 31, 2023
Citation Information: J Clin Invest. 2023;133(7):e164223. https://doi.org/10.1172/JCI164223.
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Research Article Inflammation Neuroscience

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination

Abstract

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte–Kir4.1–deficient (OL-Kir4.1–deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Authors

Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D’Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K. Sonner, Jung Hyung Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C. Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J. Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A. Calabresi, Manuel A. Friese, Ari J. Green, Claudio Acuna, David H. Rowitch, Sven G. Meuth, Lucas Schirmer

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Figure 4

Altered neuronal excitability and network activity in EAE.

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Altered neuronal excitability and network activity in EAE. (A) Cartoon i...
(A) Cartoon illustrates in vivo recordings from mouse A1. (B) Z score analysis of mouse auditory neurons before EAE induction demonstrated a tonotopic organization of the auditory cortex with a neuronal response to 10 kHz (pink insets) but not 2.5 kHz (blue insets) tones relative to baseline (green insets). EAE induction augmented overall neuronal activity and disrupted tonotopic organization (increased neuronal response to 2.5 kHz) (each, n = 34). (C and D) RTG (30 μM) reduced neuronal excitability (C) and increased M-currents (D) in control (C, untreated, n = 6; RTG, n = 7; D, untreated, n = 10; RTG, n = 9) and 12 dpi EAE (each n = 6) mouse brain sections. (E) Continuous RTG treatment (1 mg/kg) starting at baseline prevented an EAE-associated increase in neuronal excitability at 12 dpi (lower panel, right) resulting in similar z scores before EAE induction (left panels) (each, n = 34). (F) RTG (0.3 μM, n = 15; 1 μM, n = 15; 3 μM, n = 30) reduced normalized relative iEN firing in a dose-dependent manner compared with untreated iENs (n = 41). Kv channel blocker 4-AP increased spontaneous firing (each, n = 29). (G) GCaMP7s reporter iENs showed reduced spontaneous calcium transients in response to RTG (3 μM; each, n = 74). (H) Representative EPSC traces revealed reduced normalized relative EPSC frequency and amplitudes (0.3 μM, n = 15; 1 μM, n = 14 [amplitude], 15 [frequency]; 3 μM, n = 48) of RTG-treated iENs in a dose-dependent manner compared with controls (frequency. n = 56; amplitude. n = 55). Scale bar: 80 μm (G). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA (B); 1-way ANOVA (C and D); multiple unpaired t tests (E); Kruskal-Wallis (left) and Mann-Whitney U (right) tests (F); 2-way ANOVA (left) and Mann-Whitney U (right) (G); and Kruskal-Wallis test (H).